Screening out irrelevant cell-based models of disease

The common and persistent failures to translate promising preclinical drug candidates into clinical success highlight the limited effectiveness of disease models currently used in drug discovery. An apparent reluctance to explore and adopt alternative cell-and tissue-based model systems, coupled with a detachment from clinical practice during assay validation, contributes to ineffective translational research. To help address these issues and stimulate debate, here we propose a set of principles to facilitate the definition and development of disease-relevant assays, and we discuss new opportunities for exploiting the latest advances in cell-based assay technologies in drug discovery, including induced pluripotent stem cells, three-dimensional (3D) co-culture and organ-on-a-chip systems, complemented by advances in single-cell imaging and gene editing technologies. Funding to support precompetitive, multidisciplinary collaborations to develop novel preclinical models and cell-based screening technologies could have a key role in improving their clinical relevance, and ultimately increase clinical success rates

Diminishing benefits of urban living for children and adolescents’ growth and development

AbstractOptimal growth and development in childhood and adolescence is crucial for lifelong health and well-being1–6. Here we used data from 2,325 population-based studies, with measurements of height and weight from 71 million participants, to report the height and body-mass index (BMI) of children and adolescents aged 5–19 years on the basis of rural and urban place of residence in 200 countries and territories from 1990 to 2020. In 1990, children and adolescents residing in cities were taller than their rural counterparts in all but a few high-income countries. By 2020, the urban height advantage became smaller in most countries, and in many high-income western countries it reversed into a small urban-based disadvantage. The exception was for boys in most countries in sub-Saharan Africa and in some countries in Oceania, south Asia and the region of central Asia, Middle East and north Africa. In these countries, successive cohorts of boys from rural places either did not gain height or possibly became shorter, and hence fell further behind their urban peers. The difference between the age-standardized mean BMI of children in urban and rural areas was &lt;1.1 kg m–2 in the vast majority of countries. Within this small range, BMI increased slightly more in cities than in rural areas, except in south Asia, sub-Saharan Africa and some countries in central and eastern Europe. Our results show that in much of the world, the growth and developmental advantages of living in cities have diminished in the twenty-first century, whereas in much of sub-Saharan Africa they have amplified.</jats:p

The potential impact of pre-exposure prophylaxis for HIV prevention among men who have sex with men and transwomen in Lima, Peru: a mathematical modelling study.

BACKGROUND: HIV pre-exposure prophylaxis (PrEP), the use of antiretroviral drugs by uninfected individuals to prevent HIV infection, has demonstrated effectiveness in preventing acquisition in a high-risk population of men who have sex with men (MSM). Consequently, there is a need to understand if and how PrEP can be used cost-effectively to prevent HIV infection in such populations. METHODS AND FINDINGS: We developed a mathematical model representing the HIV epidemic among MSM and transwomen (male-to-female transgender individuals) in Lima, Peru, as a test case. PrEP effectiveness in the model is assumed to result from the combination of a "conditional efficacy" parameter and an adherence parameter. Annual operating costs from a health provider perspective were based on the US Centers for Disease Control and Prevention interim guidelines for PrEP use. The model was used to investigate the population-level impact, cost, and cost-effectiveness of PrEP under a range of implementation scenarios. The epidemiological impact of PrEP is largely driven by programme characteristics. For a modest PrEP coverage of 5%, over 8% of infections could be averted in a programme prioritising those at higher risk and attaining the adherence levels of the Pre-Exposure Prophylaxis Initiative study. Across all scenarios, the highest estimated cost per disability-adjusted life year averted (uniform strategy for a coverage level of 20%, US$1,036-US$4,254) is below the World Health Organization recommended threshold for cost-effective interventions, while only certain optimistic scenarios (low coverage of 5% and some or high prioritisation) are likely to be cost-effective using the World Bank threshold. The impact of PrEP is reduced if those on PrEP decrease condom use, but only extreme behaviour changes among non-adherers (over 80% reduction in condom use) and a low PrEP conditional efficacy (40%) would adversely impact the epidemic. However, PrEP will not arrest HIV transmission in isolation because of its incomplete effectiveness and dependence on adherence, and because the high cost of programmes limits the coverage levels that could potentially be attained. CONCLUSIONS: A strategic PrEP intervention could be a cost-effective addition to existing HIV prevention strategies for MSM populations. However, despite being cost-effective, a substantial expenditure would be required to generate significant reductions in incidence. Please see later in the article for the Editors' Summary

Late-glacial and early holocene climate and environment from stable isotopes in Welsh Tufa

The Caerwys tufa in North Wales (UK) contains basal deposits thought to represent carbonate precipitation during the Late-glacial interstadial. These deposits are used to test whether stable isotope data record all or part of a warming-cooling-warming trend through the transition of the Late-glacial interstadial, Younger Dryas stadial and early Holocene. The d18O values and molluscan abundance data suggest that deposition of the Late-glacial tufa occurred mainly during a relatively warm period (? GL-1c or 1e) followed by cooling, the latter likely to be the transition into the Younger Dryas stadial. Tufa deposition is not recorded in the coldest part of the stadial: it is replaced by a sandy horizon. d13C values around -8.5‰ in the basal Late-glacial interstadial tufas show there was a significant influence from isotopically light soil-zone CO2, consistent with development of birch scrub and woodland further south in North Wales. During climatic cooling into the Younger Dryas stadial a 1‰ decrease in tufa d13C is interpreted to represent decreasing phytoplankton photosynthetic activity in pools causing less isotopic enrichment of the tufa d13C. In the (pre-9000 cal. years BP) early Holocene tufas at Caerwys, palaeo-water temperatures calculated from d18O in tufa calcite and from shell carbonate of Lymnaea peregra agree well and suggest summer water temperatures in the range 13 to 16.5°C.d13C data from these early Holocene pool-micrite tufas demonstrate that phytoplanktonic photosynthetic activity within the water column resumed under the warmer conditions causing isotopic enrichment of the tufa d13C values

Climatic change recorded by stable isotopes and trace elements in a British Holocene tufa

Combined stable isotope (d18O and d13C) and trace element (Mg, Sr) geochemistry from bulk tufa calcite and ostracod shell calcite from an early Holocene British tufa reveal clear records of Holocene palaeoclimatic change. Variation in d18O is caused principally by change in the isotopic composition of Holocene rainfall (recharge), itself caused mainly by change in air temperature. The d13C variability through much of the deposit reflects increasing influence of soil-zone CO2, owing to progressive woodland soil development. Bulk tufa Mg/Ca and Sr/Ca are controlled by their concentrations in the spring water. Importantly, Mg/Ca ratios are not related to d18O values and thus show no temperature dependence. First-order sympathetic relationships between d13C values and Mg/Ca and Sr/Ca are controlled by aquifer processes (residence times, CO2 degassing and calcite dissolution/reprecipitation) and probably record intensity of palaeorainfall (recharge) effects. Stable isotope records from ostracod shells show evidence of vital effects relative to bulk tufa data. The ostracod isotopic records are markedly ‘spiky’ because the ostracods record ‘snapshots’ of relatively short duration (years), whereas the bulk tufa samples record averages of longer time periods, probably decades. The d18O record appears to show early Holocene warming, a thermal maximum at ca. 8900?cal. yr?BP and the global 8200?yr BP cold event. Combined d13C, Mg/Ca and Sr/Ca data suggest that early Holocene warming was accompanied by decreasing rainfall intensity. The Mg/Ca data suggest that the 8200?yr BP cold event was also dry. Warmer and wetter conditions were re-established after the 8200?yr BP cold event until the top of the preserved tufa sequence at ca. 7100?cal. yr BP

The Expression of Emotions in 20th Century Books

We report here trends in the usage of “mood” words, that is, words carrying emotional content, in 20th century English language books, using the data set provided by Google that includes word frequencies in roughly 4% of all books published up to the year 2008. We find evidence for distinct historical periods of positive and negative moods, underlain by a general decrease in the use of emotion-related words through time. Finally, we show that, in books, American English has become decidedly more “emotional” than British English in the last half-century, as a part of a more general increase of the stylistic divergence between the two variants of English language